JP2579729B2 - Nitroglycerin plaster and method for producing the same - Google Patents

Abstract

The invention relates to a dermal plaster for the transdermal administration of nitroglycerin, consisting of, besides a support film and a removable protective film, a nitroglycerin-containing, in particular adhesive, composition based on a crosslinked acrylate/vinyl acetate copolymer whose monomer mixture employed for the polymerisation contains 21 to 40 % by weight of vinyl acetate, 55 to 70 % by weight of a C2-8-alkyl acrylate and 3 to 10 % by weight of a C2-4-hydroxyalkyl acrylate and which is crosslinked after admixture of a conventional crosslinker and the nitroglycerin additionally by heating and removing solvents which are present. The specific adhesive composition according to the invention has not only a high absorption capacity but also a high and controllable release capacity for nitroglycerin so that the release area of the plaster necessary for the amount released each day can be kept small, and thus the costs of the plaster are very low. At the same time, owing to the simple adhesive composition, the preparation process is simplified, the addition of other substances to increase the transepidermal transport of substances is unnecessary and thus the costs of the plaster are further kept low and the risk of skin irritation is avoided.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a dermal plaster for transdermal administration of nitroglycerin, comprising a support film and a nitroglycerin-containing adhesive based on a crosslinked acrylate copolymer. The plaster also has a protective film that is removed by peeling before use, ie before its application to the skin.

Many skin plasters for transdermal administration of nitroglycerin are known. For example, DE2135533 and DE3315272 are
Disclosed is a plaster constructed from a number of layers and regulating the delivery of the active agent. Nitroglycerin is released by various mechanisms, either from a single-layer reservoir (DE2135533) through a regulatory membrane or with the specific design of a multi-layer reservoir (DE3315272). Since multi-layer skin plasters are particularly expensive to manufacture, paste plasters consisting of a single layer in addition to the support film have recently been developed. In order to allow sufficient nitroglycerin to be absorbed into the skin and again to be properly supplied, various adhesive materials having different properties with respect to the absorption of the active substance, the supply of the active substance and the adhesive properties to the skin have been developed. Has been developed. For example, reference is made to the following patent specification: GB Application No. 2095108, DE O
S No. 3231400, GB Application No. 2086224, EP Application No. 0062682
No., EP 85903926.5, EP 86902978.5, EP 028550
No., EP 0272562, US 4608249 and DE PS 3200369
issue. Depending on the materials used and the degree of cross-linking, plasters have different absorption and delivery capabilities for nitroglycerin and are characterized by varying their ability to adhere to the skin. Various skin compatibility also play a significant role. Many salves also contain a substance (ie, a resorption enhancer) to enhance the transdermal transport of the substance.

Not only has the absorption capacity as high as possible, so that the open surface of the plaster is small with the required amount to be opened per day and thus the price of the plaster is as low as possible.
Also has a high supply capacity for nitroglycerin,
It is an object of the present invention to provide a skin plaster for transdermal administration of nitroglycerin. The use of a specific adhesive at the same time simplifies the manufacturing process, makes it less expensive and saves on the basis of the addition of resorption accelerators. This simplification of the pharmaceutical preparation at the same time reduces the risk of skin irritation and / or the risk of uncontrollable changes in the nitroglycerin concentration in the adhesive body, wherein said risk is sometimes This is accompanied by penetration of the resorption promoter from the adhesive.

It comprises a support foil, a nitroglycerin-containing adhesive based on a crosslinked acrylate-vinyl acetate copolymer, and a conventional removable protective film. A dermal patch of the present invention for transdermal administration of nitroglycerin, wherein the nitroglycerin-containing adhesive material is based on 100% by weight of monomer in an organic solvent.
~ 40% by weight, acrylic acid- _C2-8 -alkyl ester 55 ~
Radical polymerization in a first stage of a mixture consisting of 70% by weight and 3-10% by weight of acrylic acid- _C2-4 -hydroxylacrylic ester, the amount required for use in conventional crosslinkers and salves in organic solvents. Of the nitroglycerin in the second stage (in an organic solvent if necessary) and the resulting mixture or a specific acrylate
Cross-linking of the vinyl acetate copolymer by heating and removal of the organic solvent or mixture of solvents used in the third stage, and the resulting nitroglycerin is identified by subsequent and additional cross-linking of the particular acrylate-vinyl acetate copolymer Characterized in that it is built into an adhesive material in the manner described above. The acrylate-vinyl acetate copolymer has a relative viscosity between 3.0 and 4.2.

Preferably, the mixture of monomers comprises 2-ethylhexyl acrylate and hydroxyethyl acrylate in addition to vinyl acetate. Preferably, the subsequent crosslinking of the particular acrylate-vinyl acetate copolymer is effected with 0.3 to 3% by weight of a titanate consisting of butyl polytitanate and / or titanium acetylacetonato, said weight being based on the weight of the copolymer. is there).

The process for preparing the plaster of the present invention comprises nitroglycerin and a conventional crosslinker or a conventional mixture of crosslinkers in the amounts required for the use of the plaster, and comprises 21-40 vinyl acetate.
Wt%, -C acrylate _2-8 - alkyl esters 55-70% by weight and -C acrylate _2-4 - obtained by radical polymerization of a mixture of monomers consisting of hydroxy alkyl esters 3-10% by weight, solution of the copolymer Is applied to the protective film of the plaster for the required layer thickness, and the solvent or mixture of solvents is removed by heating, thereby effecting additional crosslinking of the particular acrylate-vinyl acetate copolymer.

Preferably, the method comprises dissolving the acrylate-vinyl acetate copolymer, nitroglycerin and the crosslinker in a solvent comprising 20 to 40% by weight of ethanol or an ethanol-methanol mixture, and having a solids content of the particular acrylate-vinyl acetate copolymer, It is characterized in that it comprises 40 to 60% by weight of a mixture of a crosslinking agent and nitroglycerin.

The amount of preparation and starting mixture of skin patches for transdermal administration of nitroglycerin <embodiments> The present invention is referred to with respect to 100 m ^2.

4.00 kg of nitroglycerin in oil form was
It was added slowly with intensive mixing to 16.00 kg of a 40% (w / w) solution of vinyl acetate copolymer. Next, the mixture was homogenized by stirring. As a result, in this adhesive solution,
A 20% (w / w) solution of nitroglycerin was obtained.

An acrylate-vinyl acetate copolymer was prepared as follows: 112 g vinyl acetate, 2-ethylhexyl acrylate 27
0 g, 20 g of hydroxyethyl acrylate, 1.4 g of azodiisobutyronitrile and 407 g of ethyl acetate,
112 g of vinyl acetate, 2-ethylhexyl acrylate 39
g, 3 g of hydroxyethyl acrylate and 0.5 g of azodiisobutyronitrile were added to 115 g of ethyl acetate and heated to reflux. The remaining portion of the components was added over 4 hours with constant reflux. After completion of the polymerization, the mixture was cooled to room temperature. The resulting adhesive polymer solution is
25 ° C as measured by Brookfield viscometer
Had a viscosity of 5300 mPa.s, a solids fraction of 47.9% and a relative viscosity of 3.1.

To this solution was added 1.35 g of titanium acetylacetonato and sufficient ethanol or a mixture of ethanol-ethyl acetate to adjust the solids content of the product to 40%.

Example 1 The adhesive solution containing 20% (w / w) nitroglycerin was applied to a siliconized polyester film by 100 μm.
After removal of the solvent, a film having a weight per unit area of 92 g / m ² was obtained. 19 μm film
1 mm thick polyester film and punched to form a plaster having a contact area of 16 cm ² (FIG. 1).
And 2). The skin plaster so prepared having a weight of 420 mg contained 55 mg of nitroglycerin.

To assess the opening behavior of the active agent in vitro, a plaster having a punching 3.14 cm ² surface, modified F
ranz diffusion cell (Chien, Yie W., Drngs of Today 23rd
Volume, No. 11 (1987) 625-646).

Next, the cell was filled with 18.00 ml of an isotonic phosphate buffer solution (3.
2 ± 0.5 ℃), fill immediately (without bubbles),
Then, the temperature was adjusted to 32 ± 0.5 ° C. After 2,4,6 and 24 hours,
The open medium was replaced by a fresh solution temperature-controlled to 32 ± 0.5 ° C. The removed solution was investigated for its nitroglycerin content by HPLC chromatography (Lit .: Pharm. Biol. 4, 32 (1981)). Figure 3 shows a 16cm ²
1 shows the release profile measured according to the invention for plasters of size.

Average nitroglycerin opening speed (± SD) were as follows (n = 3): 2 hours after 2.32 ± 0.56mg / 16cm ² 4 hours later 4.42 ± 1.00mg / 16cm ² 6 hours after 6.43 ± 1.33 mg / 16cm ² 24 hours later 18.74 ± 2.43mg / 16cm ² Example 2 40% of polyacrylate solution and nitroglycerin
(W / w) 0.8% (w / w) titanium acetylacetonato with respect to solids (manufacturer: Dynamit Nobel Nederland BV,
75% (w / w) solution in isopropanol)
w) Added further to the adhesive solution containing nitroglycerin and homogenized the mixture. 100 of the solution
Applying to a siliconized polyester film having a thickness of μm, a film having a surface weight of 93 g / m ² was obtained after removal of the solvent. The film was covered with a 19 μm thick polyester film and punched out.
A plaster having a contact area of cm was obtained (FIGS. 1 and 2). 420m
The so-prepared skin plaster having a weight of g contained 55 mg of nitroglycerin.

The in vitro release of the active substance was carried out according to the method of Example 2. FIG. 3 also shows a graph of its corresponding opening profile.

The mean nitroglycerin release rate (± SD) was as follows (n = 3): 0.54 ± 0.20 mg / 16 cm ² after ² hours 1.20 ± 0.37 mg / 16 cm ² after 6 hours 1.78 ± 0.53 mg / 16 cm ² after 24 hours 6.60 ± 1.56 mg / 16 cm ² Example 3 Applying the adhesive solution containing 20% (w / w) nitroglycerin to a siliconized polyester film having a thickness of 100 μm and removing the solution After that, a film having a weight per unit area of 64 g / m ² was obtained. The film was covered with a 19 μm thick polyester film,
Then, punching was performed to obtain a plaster having a contact area of 16 cm ² (FIGS. 1 and 2). The so-prepared skin plaster having a weight of 360 mg contained 40 mg of nitroglycerin. The release of the active substance in vitro was carried out according to the method of Example 1. FIG. 3 also graphically illustrates the corresponding opening profile.

The average nitroglycerin release rate (± SD) was as follows (n = 3): 1.27 ± 0.29 mg / 16 cm ² after ² hours 4.48 ± 0.48 mg / 16 cm ² after 6 hours 3.56 ± 0.60 after 6 hours mg / 16cm ² After 24 hours 10.79 ± 0.82mg / 16cm ²

 ────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Voithner, Dieter Der-4019 Monheim, Lortzinkbek 52 (72) Inventor Knobelsdorf, Fau. Henning Germany 5300 Bonn 3, Lusterstrasse 40 (72) Inventor Wolf, Hans-Michael Germany, Day 4019 Monheim, Richard Bagner-Strasse 2 (72) Inventor Hoffmann, Liner Federal Republic of Germany, Day 5450 Neubit 22, Burghofstrasse 123 (72) Inventor Meconi, Reinhold Federal Republic of Germany, Day 5450 Neubit 11, Alemannenstrasse 42 (72) Inventor Klein, Robert Peter Germany 5450 Neubit 11, Bickingerstrasse 3 (56) References JP-A-3-220120 (JP, A)

Claims (10)

(57) [Claims] 1. A skin plaster for transdermal administration of nitroglycerin, comprising a support film, a nitroglycerin-containing adhesive based on an acrylate-vinyl acetate copolymer and a conventional protective film which can be removed before use. Wherein the nitroglycerin-containing adhesive comprises: 1) 21-40% by weight of vinyl acetate, 55-70% by weight of acrylic acid-C _2-8 -alkyl ester, based on 100% by weight of the monomer mixture, in an organic solvent; Radical polymerization of a mixture containing 3 to 10% by weight of acrylic acid- _C2-4 -hydroxylalkyl ester; 2) mixing of nitroglycerin in the amount required for the use of conventional crosslinking agents and salves in organic solvents; and 3) A skin plaster prepared by crosslinking the obtained mixture by heating and removing a solvent or a solvent mixture used. 2. The skin plaster according to claim 1, wherein said acrylic acid-C _2-4 -hydroxyalkyl ester is hydroxyethyl acrylate. Wherein the acrylate -C _2-4 - hydroxyalkyl esters are 2-hydroxyethyl acrylate, and said acrylate -C _2-8 - alkyl esters claims, characterized in that ethyl acrylate 2. The skin plaster according to item 1, wherein 4. The skin plaster according to claim 1, wherein said crosslinking agent is a titanate or a mixture thereof. 5. For crosslinking, a crosslinking agent is included and, based on the weight of the copolymer obtained by radical polymerization,
5. A skin plaster according to claim 4, wherein 0.3 to 3% by weight of a titanate or a mixture thereof is used. 6. A skin plaster according to claim 4, wherein said crosslinking agent is acetylacetonato titanium and / or butyl polytitanate. 7. A method for producing a plaster according to any one of claims 1 to 6, comprising nitroglycerin and a crosslinking agent in the amounts required for the use of the plaster, and an organic solvent. in, based on 100% by weight of the monomer mixture used, 21 to 40 wt% of vinyl acetate, 55 to 70 weight percent acrylic acid -C _2-8 - alkyl esters and 3 to 10
A solution of an acrylate-vinyl acetate copolymer produced by radical polymerization of a mixture of monomers consisting of acrylic acid- _C2-4- hydroxyalkyl esters by weight is applied to the protective film of the plaster at the required layer thickness. Applied, the solvent or mixture of solvents is removed by heating,
A method wherein the specific acrylate-vinyl acetate copolymer is crosslinked, after which a support film is applied and the plaster is cut to the required size and / or punched. 8. The method of claim 1, wherein said specific acrylate-vinyl acetate copolymer, nitroglycerin and a crosslinking agent are contained in an amount of 20 to 40% by weight.
In ethanol or an ethanol-methanol mixture, the solid component of which is the specific acrylate-
8. The method according to claim 7, comprising 40 to 60% by weight of a mixture of a vinyl acetate copolymer, a crosslinking agent and nitroglycerin. 9. The skin plaster according to any one of claims 1 to 6, wherein the organic solvent or the solvent mixture is substantially completely removed in the step (3). 10. A skin plaster according to any one of claims 1 to 6, wherein said organic solvent or solvent mixture is removed by heating in said step 3).